Cell-Autonomous versus Systemic Akt Isoform Deletions Uncovered New Roles for Akt1 and Akt2 in Breast Cancer.

Xinyu Chen, Majd M Ariss, Gopalakrishnan Ramakrishnan, Veronique Nogueira, Catherine Blaha, William Putzbach, Abul B M M K Islam, Maxim V Frolov, Nissim Hay

Molecular cell 2020 Oct 01

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Studies in three mouse models of breast cancer identified profound discrepancies between cell-autonomous and systemic Akt1- or Akt2-inducible deletion on breast cancer tumorigenesis and metastasis. Although systemic Akt1 deletion inhibits metastasis, cell-autonomous Akt1 deletion does not. Single-cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing survival and mobilization of tumor-associated neutrophils. Importantly, either systemic or neutrophil-specific Akt1 deletion is sufficient to inhibit metastasis of Akt-proficient tumors. Thus, Akt1-specific inhibition could be therapeutic for breast cancer metastasis regardless of primary tumor origin. Systemic Akt2 deletion does not inhibit and exacerbates mammary tumorigenesis and metastasis, but cell-autonomous Akt2 deletion prevents breast cancer tumorigenesis by ErbB2. Elevated circulating insulin level induced by Akt2 systemic deletion hyperactivates tumor Akt, exacerbating ErbB2-mediated tumorigenesis, curbed by pharmacological reduction of the elevated insulin. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Xinyu Chen, Majd M Ariss, Gopalakrishnan Ramakrishnan, Veronique Nogueira, Catherine Blaha, William Putzbach, Abul B M M K Islam, Maxim V Frolov, Nissim Hay. Cell-Autonomous versus Systemic Akt Isoform Deletions Uncovered New Roles for Akt1 and Akt2 in Breast Cancer. Molecular cell. 2020 Oct 01;80(1):87-101.e5